The shortage of effective drugs against wound infecting pathogens poses a serious public health threat. Combination treatment may represent a good choice for treating infections caused by these pathogens. The aim of the present study was to evaluate the in vitro efficacy of nimbolide, desacetylnimbin isolated from Azadirachta indica and the amide derivatives of nimbolide in combination with first generation cephalosporin antibiotics against major wound associated bacterial pathogens. The antibacterial activity of the compounds and antibiotics were studied by calculating minimum inhibitory concentration and minimum bactericidal concentration. The checkerboard and time-kill assay were used to evaluate the interactions between the compounds and antibiotics. Nimbolide recorded highest antimicrobial activity against all tested strains followed by desacetylnimbin but the amide derivatives of nimbolide were found to be less active. The MICs of test compounds ranged from 64 to 2000 µg/mL. In the checkerboard test, nimbolide and its derivatives markedly reduced the MIC values of the antibiotics. Significant synergistic effect was recorded by nimbolide as well as desacetylnimbin in combination with antibiotics and this combination recorded significant reduction of the colony forming units (CFUs) in time kill assay and the maximum reduction was recorded between 4 to 12 h. The above combination was also found to be effective against methicillin-resistant Staphylococcus aureus (MRSA), an important drug resistant bacterium. The cytotoxicity of the compounds was tested against H9c2 and recorded no toxicity up to 200 µM. In summary, the combination of nimbolide/desacetylnimbin and antibiotics demonstrated synergistic activity against the major wound associated bacteria tested in this study. Furthermore, these compounds may potentially widen the therapeutic window of antibiotics, suggesting that these combinations could be used clinically to control infections caused by wound pathogens after in vivo experiments.